Chronic IFN-γ Exposure Drives Divergent Cellular and Molecular Responses in Glioblastoma Subtypes
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PROVIDER: PRJNA1302463 | ENA |
REPOSITORIES: ENA
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Project description:Background: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis and limited treatments. Interferon-gamma (IFN-γ) plays a complex role in modulating immune and tumor responses, and its long-term impact on GBM remains unclear. Methods: Human GBM cell lines U87 and U251 were subjected to up to 28 days of chronic IFN-γ exposure and assessed for morphology, gene expression, protein dynamics, and cytokine secretion. RNA sequencing, automated Western blotting, and single-cell proteomics were employed to uncover distinct cellular and molecular adaptations to prolonged IFN-γ signaling. Results: Chronic IFN-γ exposure induced significantly divergent phenotypic changes in U87 and U251 cells. U87 cells formed neurosphere-like structures and upregulated STAT1/STAT3 signaling, suggesting an immunogenic response. In contrast, U251 cells displayed elongated morphologies and activated PI3K-Akt and Erk pathways, promoting survival and immune evasion. Differential gene expression analysis highlighted unique temporal profiles, with U251 cells exhibiting higher expression of immune resistance genes such as PD-L1 and VEGF. Secretome profiling further demonstrated contrasting cytokine landscapes: U87 cells secreted pro-inflammatory cytokines, while U251 cells produced immunosuppressive factors. Conclusions: Chronic IFN-γ exposure drives distinct molecular and phenotypic changes in GBM subtypes, reflecting their intrinsic heterogeneity. While IFN-γ enhances immune activation, prolonged exposure may also promote immune escape. These findings emphasize the need for therapeutic strategies combining IFN-γ with immune checkpoint inhibitors and targeted pathway modulation to optimize GBM treatment outcomes.
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Project description:G-protein coupled receptors (GPCRs) have diverse roles in physiological processes, including immunity. Gs-coupled GPCRs increase while Gi-coupled ones decrease intracellular cAMP. Previous studies suggest that, in epithelial cells, Gs-coupled GPCRs enhance whereas Gi-coupled GPCRs suppress pro-inflammatory immune responses. In order to examine the issue, we chose beta2 adrenergic receptor and GPR40 as representatives of Gs- and Gi- coupled GPCRs, respectively, and examined their effects on TNF-alpha and IFN-gamma-(TNF-alpha + IFN-gamma) induced gene expression by HaCaT. We used microarrays to detail the global changes of gene expression induced by a beta2 adrenergic receptor agonist terbutaline or GPR40 agonist GW9508 pre-treatment in TNF-alpha + IFN-gamma - stimulated HaCaT cells. HaCaT cells were pre-treated with terbutaline or GW9508, TNF-alpha + IFN-gamma were then added, and cultured for another 24 h. Cells were then used for RNA extraction and hybridization on Affymetrix microarrays. We sought to clarify changes in gene expression after 1) TNF-alpha + IFN-gamma, 2) TNF-alpha + IFN-gamma + terbutaline, and 3) TNF-alpha + IFN-gamma + GW9508 treatment. To this end, we set 4 groups of samples; 1) unstimulated group, 2) TNF-alpha + IFN-gamma-stimulated group, 3) TNF-alpha + IFN-gamma + terbutaline-stimulated group, and 4) TNF-alpha + IFN-gamma + GW9508-stimulated group. In each group, HaCaT cells were stimulated in triplicate wells (n=3).
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Project description:Expression data from HT-29 human colon adenocarcinoma cells treated with IFN-γ for 24 hr Total RNA was isolated from HT-29 cells after 24h stimulation with 200 U ml-1 IFN-γ (Roche). The experiment was done on three biological replicates.
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Project description:Type-I (e.g. IFN-alpha, IFN-beta) and type-II IFNs (IFN-gamma) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-gamma is thought to do so only through STAT1 homodimers while type-I IFNs activate both STAT1- and STAT2-containing complexes such as ISGF3. Here we show that ISGF3II - composed of phosphorylated STAT1, unphosphorylated STAT2, and IRF9 - also plays a role in IFN-gamma-mediated antiviral activity in humans. Using phosphorylated STAT1 as a marker for IFN signaling, western blot analysis of IFN-alpha2a treated human A549 cells revealed that pSTAT1 (Y701) levels peaked at 1h, decreased by 6h, and remained at low levels for up to 48h. Cells treated with IFN-gamma showed a biphasic pSTAT1 response with an early peak at 1-2h and a second peak at 15-24h. Gene expression microarray following IFN-gamma treatment for 24h indicated an induction of antiviral genes that are induced by ISGF3 and associated with a type-1 IFN response. Induction of these genes by autocrine type-I and type-III IFN signaling was ruled out using neutralizing antibodies to these IFNs in biological assays and by qRT-PCR. Despite the absence of autocrine IFNs, IFN-gamma treatment induced formation of ISGF3II. This novel transcription factor complex binds to ISRE promoter sequences, as shown by ChIP analysis of the PKR promoter. STAT2 and IRF9 knockdown in A549 cells reversed IFN-gamma-mediated ISRE induction and antiviral activity - implicating ISGF3II formation as a significant component of the cellular response and biological activity of IFN-gamma. Two treatments using three biological replicates each were performed using three million A549 cells. Each was seeded overnight in 10mL complete RPMI and treated. Three were treated with alpha-IFN and three treated with gamma-IFN for 24h. Control samples were left untreated.
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Project description:The source of IFN-γ in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-γ and expression microarray analysis was performed, and probes showing significantly higher values in IFN-γ-added group were termed “IFN-γ signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-γ signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-γ in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-γ-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment.
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